Efficacy and Safety of Intravenous Neridronic Acid in Complex Regional Pain Syndrome (CRPS)
NCT ID: NCT03560986
Last Updated: 2020-08-05
Study Results
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View full resultsBasic Information
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TERMINATED
PHASE3
267 participants
INTERVENTIONAL
2018-05-31
2019-08-01
Brief Summary
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The trial consisted of an Enrollment Period lasting up to 60 days, Treatment Period A consisting of 4 infusions (neridronic acid 100 mg or placebo) over 10 days, and a Follow-up Period 1 until Week 26. At Week 26, participants meeting the pre-specified criteria entered the open-label Treatment Period B with 4 additional infusions (neridronic acid) over 10 days and follow-up visits until Week 52. Participants not meeting the pre-specified criteria to continue into Treatment Period B continued in Follow-up Period 2 until Week 52.
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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Neridronic acid
Neridronic acid 100 mg - 4 intravenous (i.v.) infusions within 10 days (i.e., on Days 1, 4, 7, and 10). The investigational medicinal product (IMP) was diluted in sterile normal saline to a volume of approximately 500 mL before slow administration.
The maximum neridronic acid dose was 800 mg: 400 mg in Treatment Period A and 400 mg in Treatment Period B.
Neridronic acid 100 mg
100 mg neridronic acid supplied in glass vials in 8 mL of excipients.
Placebo
Matching placebo - 4 intravenous infusions within 10 days (i.e., on Days 1, 4, 7, and 10). The IMP was diluted in sterile normal saline to a volume of approximately 500 mL before slow administration.
Placebo
Glass vials with matching placebo.
Interventions
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Neridronic acid 100 mg
100 mg neridronic acid supplied in glass vials in 8 mL of excipients.
Placebo
Glass vials with matching placebo.
Eligibility Criteria
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Inclusion Criteria
* Male or female participant at least 18 years of age at Visit 1.
* A diagnosis of CRPS according to the clinical diagnostic criteria recommended by the International Association for the Study of Pain (IASP; "Budapest clinical criteria"), assessed at Visit 1. Signs and symptoms of CRPS must apply to an affected limb (arm or leg) and must demonstrate asymmetry with respect to the contralateral limb. The CRPS duration must be 2 years or less since onset of symptoms.
* A baseline average pain intensity score of greater than or equal to 4 using an 11-point numerical rating scale (NRS), referring to the CRPS-affected limb (average of pain recorded over 7 days). The baseline average pain intensity score will be calculated automatically by the electronic diary, which must be checked prior to allocation at Visit 2. A participant who has not met average baseline pain intensity requirements (at least 4 average pain intensity ratings) due to lack of compliance with the electronic diary may be rescheduled for Visit 2 (1 time only), with appropriate re-training to ensure compliance with use of the electronic diary.
* In stable treatment and follow-up therapy for CRPS for at least 1 month prior to allocation to treatment (Visit 2). Participants must have failed attempts with at least 2 available treatments for CRPS, 1 of which must have been a pharmacologic treatment.
* Women of child-bearing potential must have a negative urine Beta-human chorionic gonadotropin (ß-HCG) pregnancy test at Visit 1 and must be using 2 forms of medically acceptable contraception, including at least 1 highly effective method of contraception with a low failure rate, defined as less than 1% per year, and a second medically acceptable method such as use of condoms with spermicide by their male partner. A barrier method alone is not acceptable. Highly effective methods of contraception must be used for at least 1 month prior to Visit 2 and for the duration of the trial. Male participants must use condom and spermicide during intercourse and must take care that the female sexual partner uses at least 1 additional method of contraception with a low failure rate defined as above, starting with Visit 2 until at least 4 weeks after the last Investigational medicinal product (IMP) infusion.
* Participants must be able to communicate meaningfully, be able to differentiate with regard to location and intensity of the pain, and be able to answer the questions in the questionnaires used in this trial (assistance in filling out the questionnaires may be provided, if required due to motor or other physical impairment).
Exclusion Criteria
* Serum calcium or magnesium outside of the central laboratory's reference range, based on central safety laboratory data obtained prior to Visit 2 (a single repeat laboratory test is allowed); a history of hypocalcemia or a metabolic disorder anticipated to increase risk for hypocalcemia (e.g., hypoparathyroidism); anticipated need for any new drug with known potential to cause hypocalcemia (e.g., aminoglycosides, new treatment with or dose adjustment of loop diuretics) during the trial. Participants on a stable dose of loop diuretics may receive treatment with IMP as long as no dosage increases in the diuretic medication are anticipated and calcium levels are in the reference range.
* Vitamin D deficiency, defined as a 25(OH)D level less than 30 ng/mL (75 nmol/L), based on central safety laboratory data obtained prior to Visit 2 (up to 4 repeat laboratory tests are allowed). Participants with vitamin D deficiency should receive appropriate supplementation during the Enrollment Period. A vitamin D level of at least 30 ng/mL (75 nmol/L) must be documented prior to allocation to IMP.
* Corrected QT interval (according to Fridericia's formula; QTcF) greater than 470 ms (average of 3 Electrocardiogram (ECGs) obtained at Visit 1) according to central ECG reading facility evaluation or QTcF greater than 470 ms at pre-dose ECG at Visit 2 according to the investigator's judgment; serum potassium outside the central laboratory's reference range at Visit 1(a single repeat laboratory test is allowed); clinically unstable cardiac disease, including: unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, active myocardial ischemia, or an indwelling pacemaker; evidence of complete left bundle branch block; complete atrioventricular block; history of Long QT Syndrome or a relative with this condition; or any history of or other known risk factor for torsade de pointes.
* Any prior use of a bisphosphonate for treatment of CRPS, any prior administration of a bisphosphonate within the previous year, anticipated requirement for treatment with a bisphosphonate for another condition such as osteoporosis during the trial, or administration of denosumab (Prolia®) or other bone turnover suppressing drugs within 6 months prior to Visit 1.
* History of any allergic or hypersensitivity reaction to neridronic acid or other bisphosphonate, acetaminophen, or to vitamin D or calcium supplements.
* Recent tooth extraction or other invasive dental procedure (within 3 months prior to Visit 1), unhealed or infected extraction site, or significant dental/periodontal disease that may pre-dispose to need for tooth extraction or other invasive dental procedures during the trial. Participants with indeterminate, suspicious or unreliable dental history, in the opinion of the investigator, must undergo a dental examination prior to receiving treatment.
* Evidence of denture-related gum trauma or improperly fitting dentures causing injury.
* Prior radiation therapy of the head or neck (within 1 year of Visit 1).
* History of malignancy within 2 years prior to Visit 1, with the exception of basal cell carcinoma.
* Use of nerve blocks, ketamine infusions, intravenous immunoglobulin, acupuncture, electromagnetic field treatment, or initiation/implementation of radiofrequency ablation or other sympathectomy procedures, or peripheral nerve stimulation within 6 weeks prior to Visit 1.
* Evidence of current alcohol or drug abuse, or history of alcohol or drug abuse within 2 years of Visit 1, based on participant history and physical examination and according to the investigator's judgment.
* Any other severe medical condition, including severe depression, or any other severe mood disorder, that in the opinion of the investigator may affect efficacy or safety assessments or may compromise the participants safety during trial participation.
* Women who are pregnant or breastfeeding.
* Elevated aspartate aminotransferase or alanine aminotransferase greater than 2-fold upper limit of normal, based on central safety laboratory data obtained at Visit 1, or current evidence of chronic liver disease. Safety laboratory testing may be repeated prior to Visit 2, and participants will be allowed in the trial if results of 2 consecutive tests, at least 3 days apart, are less than or equal to 2-fold upper limit of normal.
* Participation in another investigational drug trial within 3 months prior to Visit 1, or any previous trial involving neridronic acid, with the exception of participants participating in study KF7013-01 who were assigned to placebo and did not receive neridronic acid.
* Participant is engaged in litigation related to their disability from CRPS in which monetary gain or loss (or other compensation) may affect their objective participation in the trial.
* Participants taking forbidden concomitant medications/therapies or not being able to follow the rules of use of concomitant treatment.
* Participants incapable of giving informed consent.
Criteria to continue into Treatment Period B
* A value of at least 4 on the pain intensity question (question number 29, GLOBAL07) of the Patient-Reported Outcomes Measurement Information System (PROMIS®) (PROMIS-29 profile) at Visit 11.
* Evidence of renal impairment (eGFR less than 30 mL/min/1.73 m2 using the 2009 CKD-EPI creatinine equation \[Levey et al. 2009\] or a urinary ACR greater than 150 mg/g), based on central safety laboratory data obtained prior to Visit 11. A single repeat laboratory test is allowed.
* Corrected QT interval (QTcF) greater than 470 ms (average of 3 ECGs obtained at Visit 10) according to the central ECG reading facility evaluation or QTcF greater than 470 ms at pre-dose ECG at Visit 11 according to the investigator's judgment; serum potassium outside the central laboratory's reference range at Visit 10 (a single repeat laboratory test is allowed); clinically unstable cardiac disease, including: unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, active myocardial ischemia, or an indwelling pacemaker; evidence of complete left bundle branch block; complete atrioventricular block; any other known risk factor for torsade de pointes.
* Participants receiving medications with a known risk of torsades de pointes within 7 days prior to re-allocation.
* Participants taking forbidden concomitant medications/therapies or not being able to follow the rules of use of concomitant treatment.
* Recent tooth extraction or other invasive dental procedure (within 3 months prior to Visit 11), unhealed or infected extraction site, or significant dental/periodontal disease that may pre-dispose to need for tooth extraction or other invasive dental procedures during the further course of the trial.
* Serum calcium outside of the central laboratory's reference range, despite appropriate supplementation between Visit 10 and Visit 11, based on the last central safety laboratory data obtained prior to Visit 11. Two repeat laboratory tests are allowed.
* Vitamin D deficiency prior to IMP re-allocation, defined as a 25(OH)D level less than 30 ng/mL (75 nmol/L), based on the last central safety laboratory data obtained prior to Visit 11, i.e., inability to normalize 25(OH)D levels to at least 30 ng/mL (75 nmol/L) despite appropriate supplementation between Visit 10 and Visit 11. Two repeat laboratory tests are allowed.
* Elevated aspartate aminotransferase or alanine aminotransferase greater than 2-fold upper limit of normal, based on central safety laboratory data obtained at Visit 10, or current evidence of chronic liver disease. A single repeat laboratory test is allowed.
* No other criterion for trial and/or IMP discontinuation is met.
18 Years
ALL
No
Sponsors
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Grünenthal GmbH
INDUSTRY
Responsible Party
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Principal Investigators
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Grünenthal Study Director
Role: STUDY_DIRECTOR
Grünenthal GmbH
Locations
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US446 - Clinical Trial Connection
Cottonwood, Arizona, United States
US453 - Physicians Research Group II, LLC
Tempe, Arizona, United States
US428 - Quality of Life Medical and Research Center LLC
Tucson, Arizona, United States
US422 - Woodland International Research Group
Little Rock, Arkansas, United States
US454 - Alliance Research Institute
Canoga Park, California, United States
US415 - Clearview Medical Research LLC
Canyon Country, California, United States
US410 - Alliance Research Centers
Laguna Hills, California, United States
US432 - Torrance Clinical Research Institute Inc.
Lomita, California, United States
Us414 - Alexander Ford Md
Los Angeles, California, United States
US441 - Samaritan Center for Medical Research
Los Gatos, California, United States
US406 - CI Trials
Santa Ana, California, United States
US411 - Syrentis Clinical Research
Santa Ana, California, United States
US420 - Mountain View Clinical Research, INC
Denver, Colorado, United States
US447 - ASCLEPES Research Centers
Brooksville, Florida, United States
US457 - Florida Spine Institute
Clearwater, Florida, United States
US430 - South Lake Pain Institute
Clermont, Florida, United States
US434 - Finlay Medical Research
Miami, Florida, United States
US407 - Oceane 7 Medical and Research Center, Inc.
Miami, Florida, United States
US436 - Cordova Research Institute
Miami, Florida, United States
US417 - Tampa Pain Relief Center
Tampa, Florida, United States
US403 - Palm Beach Research Center
West Palm Beach, Florida, United States
US404 - Infinite Clinical Trials
Riverdale, Georgia, United States
US424 - Georgia Neurology and Sleep Medicine Assoc.
Suwanee, Georgia, United States
US431 - Injury Care Research, LLC
Boise, Idaho, United States
US437 - Great Lakes Clinical Trials LLC
Chicago, Illinois, United States
US435 - Centex Studies Inc
Lake Charles, Louisiana, United States
US448 - The Center for Rheumatology and Bone Research
Wheaton, Maryland, United States
US450 - SRI International
Plymouth, Michigan, United States
US449 - Michigan Pain Consultants
Wyoming, Michigan, United States
US433 - Creighton University - Osteoporosis Research Center
Omaha, Nebraska, United States
US419 - Manhattan Behavioral Medicine
New York, New York, United States
US440 - OnSite Clinical Solutions LLC
Charlotte, North Carolina, United States
US405 - OnSite Clinical Solutions LLC
Hickory, North Carolina, United States
US416 - Medical Research International
Oklahoma City, Oklahoma, United States
US429 - Lehigh Valley Health
Allentown, Pennsylvania, United States
US438 - Abington Neurological Associates, LTD.
Willow Grove, Pennsylvania, United States
US425 - PCPMG Clinical Research Unit LLC
Greenville, South Carolina, United States
US423 - Biopharma Informatic Inc. Research Center
Houston, Texas, United States
US443 - Centex Studies Inc
Houston, Texas, United States
US421 - Northwest Clinical Research Center
Bellevue, Washington, United States
US445 - Exemplar Research Inc
Morgantown, West Virginia, United States
CA404 - Jeffrey Weinberg Medicine Professional Corporation c/o Jacobs Pain Center
Markham, Ontario, Canada
CA406 - Malton Medical Centre (attn: Vrijender Singh)
Mississauga, Ontario, Canada
CA402 - SKDS Research Inc
Newmarket, Ontario, Canada
CA407 - King Street Medical Clinic
Oshawa, Ontario, Canada
CA403 - Bluewater Clinical Research Group
Sarnia, Ontario, Canada
CA405 - Canadian Centre for Clinical TrialsCCCT
Thornhill, Ontario, Canada
CZ403 - CCBR Ostrava
Ostrava, , Czechia
CZ402 - CCR Czech a,s.
Pardubice, , Czechia
CZ401 - FORBELI s.r.o.
Prague, , Czechia
PL405 - Medical Solutions
Elblag, , Poland
PL404 - Zagiel Med Sp Zoo
Lublin, , Poland
PL403 - Alergo-Med Specjalistyczna Przychodnia Lekarska Sp.z o.o
Tarnów, , Poland
RS401 - Clinical Center of Serbia, Clinic for physical medicine and rehabilitation
Belgrade, , Serbia
RS403 - Clinical Center Kragujevac, Department of Physical Medicine and rehabilitation
Kragujevac, , Serbia
RS404 - Clinical Center Nis, Clinic for Physical Medicine and Rehabilitation
Niš, , Serbia
RS405 - Clinical Center of Vojvodina, Medical Rehabilitation Clinic
Novi Sad, , Serbia
SK402 - MUDr. Beata Dupejova, neurologicka ambulancia sro
Banská Bystrica, , Slovakia
SK404 - Medical Center Konzilium
Dubnica nad Váhom, , Slovakia
SK403 - NEURES, s.r.o.
Krompachy, , Slovakia
SK401 - MUDr. Viliam Cíbik, PhD, Algeziologická ambulancia
Pruské, , Slovakia
GB413 - MAC Clinical Research
Barnsley, , United Kingdom
GB412 - MAC Clinical Research
Blackpool, , United Kingdom
GB415 - MAC Clinical Research
Cannock, , United Kingdom
GB416 - Royal Devon and Exeter Hospital
Exeter, , United Kingdom
GB410 - MAC Clinical Research
Leeds, , United Kingdom
GB409 - MAC Clinical Research
Liverpool, , United Kingdom
GB407 - Pain and Neuromodulation Centre Ground Floor, Gassiot House, St Thomas Hospital
London, , United Kingdom
GB402 - St Pancras Clinical Research
London, , United Kingdom
GB408 - MAC Clinical Research
Manchester, , United Kingdom
GB414 - MAC Clinical Research
Stockton-on-Tees, , United Kingdom
Countries
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References
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Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009 May 5;150(9):604-12. doi: 10.7326/0003-4819-150-9-200905050-00006.
Provided Documents
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Document Type: Statistical Analysis Plan: Final-Analysis-KF7013-04
Document Type: Statistical Analysis Plan: Pooled-Interim-Analysis-KF7013-02-KF7013-04
Document Type: Study Protocol
Other Identifiers
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2017-004244-37
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
U1111-1203-5020
Identifier Type: OTHER
Identifier Source: secondary_id
KF7013-04
Identifier Type: -
Identifier Source: org_study_id
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